Apparatus and methods for making, storing, and administering freeze-dried materials such as freeze-dried plasma

ABSTRACT

A freeze-dried material is stored in a first chamber of a container along with a reconstituting liquid for the freeze-dried material, which is stored in a second chamber of the container. A sealing wall within the container forms a barrier between the first chamber and the second chamber preventing contact between the freeze-dried material and the reconstituting liquid. At least one valve assembly in the sealing wall selectively opens a region of the sealing wall to establish fluid flow communication between the first and second chambers, allowing the freeze dried material to be reconstituted. The reconstituted freeze-dried material can be administered from the same container to a recipient.

RELATED APPLICATIONS

This application is a continuation-in-part of co-pending U.S. patentapplication Ser. No. 11/725,352, filed Mar. 19, 2007, and entitledApparatus and Methods for Making, Storing, and AdministeringFreeze-Dried Materials Such as Freeze-Dried Plasma, which isincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to methods, systems, and apparatuses formanufacturing, storing and administering freeze-dried materials, such assingle donor units of freeze-dried human plasma.

BACKGROUND OF THE INVENTION

First aid is critical for the survival of a person that has suffered aserious injury, such as a trauma victim. For instance, initial treatmentof a severely wounded person in combat situations can often mean thedifference between life and death. While it is necessary to treat thewounds and stop the bleeding of the person, it is also important toensure that the person's body is capable of properly functioning. Thus,it is necessary to take steps to ensure that the person's body isproperly hydrated after losing fluids due to the injury. The presentinvention addresses these issues.

Previously, fluids were replenished within the patient by deliveringsaline intravenously. While effective, research has indicated thatdelivery of plasma to the patient is even more effective in replenishingfluid to the patient than the use of saline. However, delivery andstorage of the plasma is critical to prevent contamination of theplasma. An ideal way of delivering the plasma is to deliver the plasmain a freeze dried form and reconstituting the plasma when it isadministered to a person.

SUMMARY OF THE INVENTION

The invention provides methods, systems, and apparatuses formanufacturing, storing and administering freeze-dried materials, such assingle donor units of freeze-dried human plasma.

According to one aspect of the invention, a freeze-dried material, e.g.,freeze-dried human plasma, is stored in a first chamber of a containeralong with a reconstituting liquid for the freeze-dried material, e.g.,de-gassed water. The reconstituting liquid is stored in a second chamberof the container. A sealing wall within the container forms a barrierbetween the first chamber and the second chamber preventing contactbetween the freeze-dried material and the reconstituting liquid. Atleast one valve assembly in the sealing wall can be manipulated toselectively open at least one region of the sealing wall to establishfluid flow communication between the first and second chambers. Thisallows the freeze dried material to be reconstituted within thecontainer. The reconstituted freeze-dried material can also beadministered directly from the same container to a recipient.

In one arrangement, the valve assembly includes a pressure sensitivevalve, e.g., a flap valve. The valve is operative between a normallyclosed condition, normally resisting fluid flow communication betweenthe first and second chambers, and an opened condition, establishingfluid flow condition communication between the first and secondchambers. The pressure sensitive valve can be placed in its opencondition in response to establishing a pressure differential across thevalve, e.g., by preferentially squeezing a chamber of the container.

In one arrangement, the valve assembly includes a normally closedseptum. The septum is operative in a normally closed condition,maintaining closure between the first and second chambers, and an openedcondition establishing fluid flow communication between the first andsecond chambers in response to at least a partially tearing of theseptum. The septum can, e.g., include a tear member coupled to a pullingmember to at least partially tear open the septum.

The pressure sensitive valve and the septum can be arranged serially toprovide a redundant valve assembly. In this arrangement, the normallyclosed septum is operative in a normally closed condition, maintainingclosure between the first and second chambers, independent of the valveand an opened condition establishing fluid flow communication betweenthe first and second chambers in response to at least a partiallytearing of the septum and a pressure differential applied across thevalve.

In one arrangement, an outer skirt is provided that overlays an exteriorwall of the container in a region of the sealing wall. The outer skirtcan include a tear member coupled to a pulling member to tear open theouter skirt for removal.

Another embodiment of the invention provides a method that provides aflexible container as above generally described, with first and secondchambers. The first chamber holds a freeze-dried material, such asfreeze-dried human plasma, in a dry state. The second chamber holds areconstituting liquid for the freeze-dried material. An interior sealingwall within the container is sized and configured to form a barrierbetween the first chamber and the second chamber preventing contactbetween the freeze-dried material and the reconstituting liquid. Atleast one valve assembly in the sealing wall is operative bymanipulation to open at least one region of the sealing wall toestablish fluid flow communication between the first and secondchambers. According to this aspect of the invention, the valve assemblyis manipulated to open the region, and the reconstituting liquid isexpressed from the second chamber through the valve assembly into thefirst chamber into contact with the freeze-dried material.

In one arrangement, an outer skirt overlays an exterior wall of thecontainer in a region of the sealing wall and blocking manipulation ofthe valve assembly. In this arrangement, the outer skirt is removed toexpose the valve assembly to manipulation prior to manipulating thevalve assembly to open the region in the sealing wall.

In another arrangement, the reconstituted freeze-dried plasma isadministered directly from the container to a recipient.

According to another aspect of the invention, a freeze-dried materialcomprising freeze-dried human plasma is prepared and stored,transported, reconstituted, and administered using a container as justgenerally described in any of the foregoing paragraphs. In onearrangement, liquid human plasma is loaded in molds. The molds arecooled until they reach approximately −45° C. The plasma is dried so themoisture content is below 5% w/w, thereby forming the freeze-dried humanmaterial that can be stored, transported, reconstituted, andadministered using a container. In another arrangement, liquid humanplasma is freeze-dried in situ within the container.

According to another aspect of the invention, a freeze-dried material,e.g., freeze-dried human plasma, is stored in a first container, and areconstituting liquid for the freeze-dried material, e.g., de-gassedwater is stored in a separate second container. A transfer set can bemanipulated to couple the two containers together, to establish fluidflow communication between the first and second containers. This allowsthe freeze dried material to be reconstituted within one of thecontainers. The reconstituted freeze-dried material can also beadministered directly from the same container to a recipient.

These and other areas of importance and significance will becomeapparent from following description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front elevation view of a device for storing freeze-driedmaterial, e.g., freeze-dried human plasma, and a reconstituting liquidfor the freeze-dried material, making possible a reconstitution of thefreeze-dried material within the device and an administration of thereconstituted freeze-dried material directly from the device to arecipient, the device being shown prior to the removal of an outerprotective skirt.

FIG. 2 is side elevation view of the device shown in FIG. 1.

FIG. 3 is a front elevation view of the device shown in FIG. 1, showingthe tearing of the outer protective skirt for its removal prior tomanipulating the device to reconstitute the freeze-dried materials.

FIG. 4A is a front elevation view of the device shown in FIG. 3, afterthe removal of the outer protective skirt and prior to manipulating thedevice to reconstitute the freeze-dried materials.

FIG. 4B is side elevation view of the device shown in FIG. 4A.

FIG. 5A is a side elevation section view of the interior sealing walland associated valve assembly formed within the device taken generallyalong line 5A-5A in FIG. 1, prior to the removal of the outer protectiveskirt.

FIG. 5B is a side elevation section view like that shown in FIG. 5A,showing an alternative arrangement of the interior sealing wall andmultiple valve assemblies.

FIG. 6 is a side elevation section view of the interior sealing wall andassociated valve assembly formed within the device taken generally alongline 6-6 in FIG. 4A, after the removal of the outer protective skirt andprior to manipulating the device to reconstitute the freeze-driedmaterials.

FIG. 7 is a side elevation section view of the interior sealing wall andassociated valve assembly like that shown in FIG. 6, after opening atleast one region of interior sealing wall and prior to manipulating thedevice to reconstitute the freeze-dried materials.

FIG. 8 is a front elevation view of the device shown in FIG. 1, showingthe removal of the outer protective skirt prior to manipulating thedevice to reconstitute the freeze-dried materials.

FIG. 9 is a front elevation view of the device shown in FIG. 8, showingthe manipulation of the valve assembly to open at least one region ofthe interior sealing wall, in the manner also shown in FIG. 7.

FIGS. 10 to 15 are front elevation view of the device shown in FIG. 9,showing the manipulating the device to reconstitute the freeze-driedmaterials.

FIG. 16 is a front elevation view of the device shown in FIG. 15,showing the administration of reconstituted material directly from thedevice to a recipient.

FIGS. 17A to 17E are diagrammatic perspective views to an illustrativeprocess for the preparation of a freeze-dried plasma cake from liquidhuman plasma, prior to insertion and storage within the device shown inFIG. 1.

FIGS. 18 and 19 are front elevation views of placing a freeze-driedmaterial (like the plasma cake formed using the process FIGS. 17A to17E) in the first chamber of the device shown in FIG. 1.

FIG. 20 is a front elevation view of placing a reconstituting liquid forthe freeze-dried material in the second chamber of the device shown inFIG. 1.

FIG. 21 is a front elevation view of placing the outer protective sleeveabout the device, to create the device shown in FIG. 1.

FIG. 22 is a front elevation view of an alternative device for storingfreeze-dried material, e.g., freeze-dried human plasma, and areconstituting liquid for the freeze-dried material, making possible areconstitution of the freeze-dried material within the device and anadministration of the reconstituted freeze-dried material directly fromthe device to a recipient, the device being shown prior to the removalof an outer protective skirt.

FIG. 23 is a front elevation interior section view of the valve assemblyformed in the device taken generally along line 23-23 in FIG. 22, priorto the removal of the outer protective skirt.

FIG. 24 is a front elevation view of the device shown in FIG. 22, afterthe removal of the outer protective skirt and prior to manipulating thedevice to reconstitute the freeze-dried materials

FIG. 25 is a front elevation interior section view of valve assemblylike that shown in FIG. 23, taken generally along line 25-25 in FIG. 23after removal of the outer protective skirt.

FIGS. 26 and 27 are front elevation interior section views showing thepassage of materials through the valve assembly shown in FIG. 25 bymanipulating the device to reconstitute the freeze-dried materials.

FIGS. 28A and 28B are a largely schematic views of an alternative way ofpackaging the reconstituting liquid for the freeze-dried material in thesecond chamber of the device of the type shown in FIG. 1 or 22.

FIGS. 29A and 29B are largely schematic views of another alternative wayof packaging the reconstituting liquid for the freeze-dried material inthe second chamber of the device of the type shown in FIG. 1 or 22.

FIG. 30 is a front elevation view of a system for storing freeze-driedmaterial, e.g., freeze-dried human plasma, and a reconstituting liquidfor the freeze-dried material, comprising individual first and secondcontainers and a transfer set that makes possible a reconstitution ofthe freeze-dried material within the system for administration to arecipient.

FIG. 31 is a front elevation view of the system shown in FIG. 30, withthe first and second containers joined in fluid communication by thetransfer set to reconstitute the freeze-dried material.

FIG. 32 is a front elevation view of one of the containers of the systemshown in FIGS. 30 and 31, after the freeze-dried material has beenreconstituted, showing the administration of reconstituted materialdirectly from the container to a recipient.

FIG. 33 is a front elevation view of a device for storing freeze-driedmaterial, e.g., freeze-dried human plasma, and a reconstituting liquidfor the freeze-dried material, the device being sized and configured forfreeze-drying material in situ within the device.

FIG. 34 is a front elevation view of the device shown in FIG. 33,showing the conveyance of liquid plasma into the device forfreeze-drying in situ within the device.

FIG. 35 is a perspective view of several devices shown in FIG. 34 afterplacement in a freeze-dryer for the purpose of freeze-drying liquidplasma in situ within each of the devices.

FIG. 36 is a front elevation view of a device shown in FIG. 35 afterremoval from the freeze-dryer, showing the freeze-dried plasma cake thathas been formed in situ within the device, and prior to the conveyanceof a reconstituting material into the device.

FIG. 37 is a front elevation view of a device shown in FIG. 36 after theconveyance of a reconstituting material into the device.

FIG. 38 is a front elevation view of placing an outer protective sleeveabout the device shown in FIG. 37, after conveyance of thereconstituting material into the device, to create the device of a typeshown in FIG. 1.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Although the disclosure hereof is detailed and exact to enable thoseskilled in the art to practice the invention, the physical embodimentsherein disclosed merely exemplify the invention which may be embodied inother specific structures. While the preferred embodiment has beendescribed, the details may be changed without departing from theinvention, which is defined by the claims.

I. Device for Storing and Reconstituting Freeze-Dried Plasma

FIGS. 1 and 2 show a device 10 for storing and administering afreeze-dried material. The device 10 comprises a flexible bag having afirst collapsible chamber 12 and a second collapsible chamber 14.

The first chamber 12, also referred to as the dry chamber, contains analiquot of a freeze-dried material 16. The nature and type offreeze-dried material 16 can vary. In the illustrated embodiment, thefreeze-dried material comprises human plasma, and the aliquot is asingle donor unit of human plasma.

The second chamber 14, also referred to as the wet chamber, contains areconstituting liquid 18 for the freeze-dried material 16. The natureand type of the reconstituting material 18 can vary. In the illustratedembodiment, the reconstituting material 18 comprises degassed, sterilewater. In use, the sterile water in the wet chamber 14 is mixed with thefreeze-dried plasma in the dry chamber 12 to provide plasma fortransfusion. The plasma is reconstituted and administered on site usingthe device 10.

The first chamber 12 is sized and configured to maintain thefreeze-dried material 16, prior to its reconstitution, in a vacuumpacked, aseptic, moisture-free and low concentration oxygen environment,preferably accommodating long term storage, e.g., at least 2 years atroom temperature. Stored in this environment, the freeze-dried material16 retains its desired qualities for transfusion.

The second chamber 12 is sized and configured to maintain thereconstituting liquid 18, prior to its mixing with the freeze-driedmaterial 16, in an aseptic environment and at a low gas concentration,preferably accommodating long term storage, e.g., at least 2 years atroom temperature.

The volume of each of the chambers 12 and 14 is preferably approximately50% larger than the volume of the freeze-dried material 16 in the firstchamber 12. This provides ample volume within the device 10 for mixingthe freeze-dried material 16 and reconstituting liquid 18, either in thefirst chamber 12 or the second chamber 14, as will be described ingreater detail later.

The device 10 may be made, e.g., of an inert medical grade plasticmaterial, such as polyvinyl chloride, polyethylene, polypropylene, orhigh density polyethylene. The device 10 can comprise a multi-laminateof polymer layers for greater durability, e.g., to resist tearing andpuncturing that could be encountered in normal handling.

The material of the device 10 can be selected to be transparent, ifdesired, to allow visual inspection of the contents of the chamber 12and 14. The material in the first chamber 12 can be selected to providea gas-impermeable barrier, such as a metallized, reducedgas-permeability coating, or a metal laminate. In this case, the wall ofthe first chamber may be opaque.

Furthermore, the device 10 may be enveloped prior to use by a vacuumsealed over-wrap 20 (shown in phantom lines in FIG. 1), made, e.g., ametallized, gas impermeable material. The over-wrap 20 enhancesshelf-stability.

An interior sealing wall 22 (see FIG. 1) compartmentalizes the device 10into the first and second chambers 12 and 14 (see also FIG. 5A). Thesealing wall 22 provides a barrier between the first chamber 12 and thesecond chamber 14, which normally prevents contact between thefreeze-dried material 16 and the reconstituting liquid 18 duringstorage, up to the instant of use.

As FIGS. 5A/B and 7 show, one or more regions 24 of the sealing wall 22may be selectively opened by a caregiver, as will be described ingreater detail later. The region(s) 24, when opened, make possible fluidcommunication between the two chambers 12 and 14. The fluidcommunication makes it possible to mix the reconstituting liquid 18 withthe freeze-dried material 16, as will further be described in greaterdetail later.

The region(s) 24 of the sealing wall 22 may be opened in various ways.In a representative embodiment (see FIG. 5), the sealing wall 22includes a normally closed valve assembly 26 associated with each region24 where the sealing wall 22 is to be opened. In FIG. 5A, a singleregion 24 is shown, so a single valve assembly 26 is shown. As shown inFIG. 5B, where multiple regions 24 a and 24 b are provided, each region24 a and 24 b would include its own dedicated valve assembly 26 a and 26b, respectively.

In the representative embodiment (see FIGS. 5A and 5B), each valveassembly 26 includes a primary, pressure sensitive valve 28. The valve28 can take the form, e.g., of a short duck bill or two way flap valve.The primary valve 28 is sized and configured to normally resist flowcommunication between the two chambers 12 and 14.

In the representative embodiment, each valve assembly 26 also includes anormally closed septum 30 between the valve 28 and the wet chamber 14.The septum 30 maintains closure between the two chambers 12 and 14,independent of the valve 28. Independent of the valve 28, the septum 30prevents unintended passage of material between the two chambers 12 and14, thereby maintaining the separate integrity of the freeze-driedmaterial 16 and the reconstituting liquid 18 within the device 10 priorto use.

The septum 30 includes an integrated tear member 32 that is incorporatedwithin the septum 30. The integrated tear member 32 is coupled to a pullstring 34 that extends through a fluid sealed pass-through or septum 36in the wall of the second chamber 14. As FIG. 1 shows, the pull stringterminates outside the device 10 at a pull tab 38.

As FIGS. 6 and 7 show, the tear member 32 is sized and configured toopen the septum 30 when a caregiver pulls on the tab 38. Thepass-through or septum 26 seals around the pull string 34, and alsoseals close after passage of the pull string 34 from the interior of thechamber 14, maintaining in integrity of the second chamber 14. Openingthe septum 30 in this manner forms the open region 24 (see FIG. 7). Theopen region 24 places the first and second chambers 12 and 14 intocommunication through the valve 28.

With the region 24 opened (see FIG. 7), the primary valve 28 stillserves to normally resist flow communication between the two chambers 12and 14. However, when the region 24 is opened, the valve 28 is sized andconfigured to resiliently yield in response to a difference in fluidpressure between opposite sides of the valve 38 (see FIGS. 11 and 14).In response to the pressure differential, the valve 28 opens in thedirection of the fluid pressure differential, from the region of higherpressure toward the region of lower pressure.

As will be described in greater detail later (as shown, respectively, inFIGS. 10 and 13), the caregiver creates the fluid pressure differentialacross the valve 28 by selectively squeezing one chamber and not theother chamber. Fluid is expelled in response to the fluid pressuredifferential through the valve 28 from the chamber that is squeezed intothe chamber that is not squeezed.

The multi-component valve assembly 26 provides a redundant sealingcapability, to assure that the chambers 12 and 14 remain separated untilit is desired to reconstitute the freeze-dried material 16.

In a representative embodiment (see FIGS. 1 and 2), the device 10further includes an outer tear-away skirt 40, which provide furtherredundancy. As FIGS. 1 and 2 show, the skirt 40 overlays the device 10in the region of the sealing wall 22. The skirt 40 serves to overlay andprotect the components of the valve assembly 26 associated with thesealing wall 22.

At least one region of the skirt 40 is circumferentially attached aboutan exterior wall of the device, e.g., by adhesive, either in the regionof the first chamber, the second chamber, or both. Furthermore, as theskirt 40 is installed about the device 10, the exterior wall of thedevice is desirably plicated or pleated or otherwise bunched together(as FIGS. 1 and 2 show). Alternatively, the placations can be performedin the wall of the container.

The placations relieve wall stress in the region of the sealing wall 22.The skirt 40, once attached, maintains these placations or pleats, andthereby serves to relieve or distribute wall stresses in the region ofsealing wall 22 and the components of the valve assembly 26 associatedwith the sealing wall 22. Such wall stresses can arise, e.g., due to theweight of the reconstituting liquid 18 contained in the second chamber14, and/or by virtue of handling during transport and manipulation priorto use. The presence of the overlaying skirt 40 also serves to isolatethe components of the valve assembly 26 associated with the sealing wall22 from unintended contact during transport and prior to use.

As FIG. 1 shows, the skirt 40 includes an integrated tear member 42. Theintegrated tear member 42 includes a pull string 44 that terminates witha pull tab 46, that depends outside the skirt 40. The tear member 42 issized and configured to tear open the skirt 40 when a caregiver pulls onthe tab 46 (as FIG. 3 shows). Upon removal of the skirt 40, theplacations of the walls of the bags 12 and 14 are relieved (as FIGS. 4Aand 4B show), placing the components of the valve assembly 26 associatedwith the sealing wall 22 into condition for manipulation.

It should be understood that reference to the first chamber 12 and thesecond chamber 14 is done to distinguish one chamber from the other, andnot to limit either chamber to a specific spatial relationship. Forexample, the chambers 12 and 14 may be arranged face to face, havingvertical edges in contact.

The technical features of the device 10 includes separate chambers orcompartments that are separated by sealing means that will allow foreventual interconnection and intercommunication, between the chambers,which can be accomplished in various ways. Furthermore, reference to abag or chambers should not be limited to any specific structure or shapebut should be understood to refer any container capable of carrying andmixing the contents 16 and 18.

II. Preparing and Packaging the Freeze Dried Material and ReconstitutingLiquid

Preparing and packaging the freeze-dried material 16 and reconstitutingliquid 18 comprises two main processing steps: (i) freeze-drying thematerial 16, and (ii) packaging the material 16 and the reconstitutingliquid 18 within the chambers 12 and 14.

A. Preparation of Freeze-Dried Plasma

In a representative embodiment, the freeze-dried material 16 comprisesplasma. A description of an illustrative way of preparing freeze-driedplasma for packaging in the device 10 therefore follows.

Preparation and manufacturing of the plasma will take place in a sterilesetting. Preferably, manufacturing and preparation procedures will bedone in an ISO Class 5 clean room (or better) with ISO Class 3bio-containment hoods for aseptic handling of human plasma. Freezedrying will be done aseptically in a CIP/SIP freeze dryer.

Human plasma is collected from a single donor in a conventional way,e.g., by collecting a unit of whole blood from the donor in a closedsystem collection bag, followed by centrifugal separation of the plasmaand its collection in an integrally connected transfer bag (containingone plasma unit of about 250 ml). Each unit (contained in the transferbag) will be handled individually in the bio-containment hood. Betweenhandling one single donor unit and another unit single donor unit from adifferent donor, there will be a line clearance protocol for change-overin the bio-containment hood. This protocol will address removal of alltools and materials associated with the previous handling. It will alsoaddress the thorough wash down of the containment work area and workarea instruments (mass balances) to ensure no residues of the previoushandling were left in place. The identification of single donor sampleswill be maintained by bar coding and other tagging of the single donorhuman plasma containers.

As shown in FIG. 17A, prior to freeze drying, the 250 ml human plasmaunit is dispensed from the transfer bag 48 into a sterile, pyrogen free,rectangular mold 50 (e.g., 4 cm×10 cm×12.5 cm—d×w×1). The mold 50 can bestainless-steel; however it can also be composed of metal with goodthermal transfer properties such as aluminum, aluminum alloy, titaniumor gold. The mold 50 may be coated on its inside surfaces with a tough,inert barrier film with good release properties such as PTFE or diamond.

As shown in FIG. 17B, the mold 50 containing the human plasma is thenplaced inside a water-impermeable, vapor-permeable, sterile, heatsealable bag 52 with bar coding and tagging 54 indicative of the humanplasma identification (source, blood type, date of collection, etc.).This vapor permeable bag 52 would typically be manufactured usingmicroporous PTFE membrane material (e.g. Gore-Tex™) or microporous HDPEmembranes (e.g. Tyvek™).

The bag 52 is heat sealed to contain the mold 50 and human plasma. Thebag 52 is designed to neatly contain the mold 50 and its contentswithout any bunching or sagging of the bag material below the surface ofthe interior mold wall edge or at the base of the mold.

As shown in FIG. 17C, the mold 50 inside the containment bag 52 is thenplaced inside a freeze dryer 56 on an aseptic freeze dryer shelf surface58. The freeze dryer 56 used for the lyophilization will be a validatedclean in place, steam in place freeze dryer with shelf area of near 200square feet or more. Such a freeze dryer 56 can accommodate at least 500molds when it is fully loaded.

Once loaded, the freeze dryer cycle is started. This cycle generallycools the human plasma to near −45° C. and freezing for 2 to 8 hours,followed by cooling of the freeze dryer condenser and application ofvacuum to start the freeze drying cycle. A freeze-dried human plasmacake 60 is formed.

In the primary freeze drying cycle, the temperature of the human plasmacake 60 needs to remain below −33° C. (the collapse temperature) tomaintain its integrity.

When the moisture content of the cake 60 is below 5% weight per weight(w/w), a secondary drying cycle (the elevated temperature) is used tofurther lower the moisture content. Generally the combined primary andsecondary freeze drying cycles will take at least 72 hours. At theconclusion of the freeze drying cycle, the freeze dryer vacuum is openedto an atmosphere of an oxygen-free, high purity inert gas such asnitrogen or argon.

As shown in FIG. 17D, the freeze dried cakes 60 in their molds 50 andcontainment bags 52 are removed to an aseptic containment cart 62 whoseenvironment may be maintained under a nitrogen or argon blanket toexclude moisture and oxygen. The containment cart 62 may couple to thefront of the freeze dryer to allow for transfer of the freeze dryercontents under a controlled inert gas blanket.

The containment carts 62 may be used to store human freeze dried plasmacakes (each cake within a mold 50 and enclosed within a bag 52) as wellas allow cakes to be transferred to a device loading area, which allowsloading of the freeze dried plasma cake 60 into the device 10, as willbe described in greater detail later.

B. Packaging Freeze-Dried Plasma and Water Into the Device

As shown in FIG. 1, the device 10 comprises a first aseptic vacuum port64, which communicates with the first chamber 12, and a second asepticvacuum port 66, which communicates with the second chamber 14. Thevacuum ports 64 and 66 are sized and configured for connection tovarious tubing T during final assembly (see FIGS. 18 to 21) tofacilitate packaging of the freeze-dried plasma material 16 andreconstituting liquid 18 (e.g., water) within the device 10.

An administration port 68 is also heat sealed in communication with thesecond chamber 14. The administration port 68 is used during thepackaging process to convey the reconstituting liquid 18 into the secondchamber 14, as will be described in greater detail later. After thereconstituting liquid 18 is packaged within the chamber 14, theadministration port 68 is sealed with a conventional septum or frangiblemembrane assembly or a convention screw-lock luer fitting 70, toaccommodate its coupling to an administration set 72 to the port 28 attime of transfusion, as shown in FIG. 16.

The device 10 also comprises a heat sealable aseptic flange 74 (see FIG.1), which allows a freeze-dried plasma cake 60 to be inserted into thefirst chamber 12, as shown in FIG. 18, and then sealed in a sterilefashion, as shown in FIG. 19.

A slot 76 may be pre-formed on the flange 74. The slot 76 makes itpossible to hang the device 10 at a desired gravity head height foradministering reconstituted plasma to an individual, as FIG. 16 shows.

Individual single donor human plasma freeze dried cakes 60 areaseptically loaded into the device 10 (see FIG. 18) through the flange74. The device loading area may be, e.g., a bio-containment hood thatexcludes significant oxygen and moisture contamination by inert gasblanketing. Also the device loading area may be an aseptic glove-boxsystem with an inert gas environment.

FIGS. 18 and 19 depict a representative loading process. The bag 52 isopened, and the plasma cake 60 removed from the mold 50. The plasma cake60 is loaded through the open flange 74 into the first chamber 12. Asshown in FIG. 17E, it is anticipated that the plasma cake 60 can betransferred into the chamber 12 directly from the mold 50 (after removalof the bag 52) using a single-use, aseptic, clear-plastic applicatortool 78, similar to a large open-ended spatula. Once the chamber 12 isloaded, the flange 74 can be sealed closed using various conventionalaseptic techniques, e.g., dielectric welding or heat sealing.

The loading of the plasma chamber 12 can be through an “oyster style”opening that comprises approximately 50% of the flange 74 of the chamber12, which can be readily sealed close after loading. An oyster openingwould allow loading of the plasma cake 60 without concerns of damagingthe first chamber 12 or the freeze-dried plasma during the process. Inthe case of the oyster opening, there would be sufficient excess overlayof the edge seam to allow for straightforward edge-seam alignment andcontact during the sealing process.

Preferably, after loading and sealing of the chamber 12, an asepticvacuum is applied through tubing T connected to the vacuum port 64 onthe first chamber 12 (see FIG. 19). Upon achieving near 100 mTorr ofpressure, the vacuum port 64 is heat sealed and the tubing T removed.This evacuation process provides for the eventual ability to mix andreconstitute the human freeze dried plasma without introduction ofbubbles and without foaming. The vacuum would also cause the plasma cake60 to be compacted to a fine powder, forming the freeze-dried material16 within the chamber 12.

To maintain a direct traceable link between the source plasma and thematerial 16 packaged into the chamber 12, the device 10 preferablyincludes a bar coding and tagging 54′ (see FIG. 1), which is indicativeof the human plasma identification (source, blood type, date ofcollection, etc.), and which replicates or is otherwise linked to thebar coding and tagging 54 placed on the bag 52 enveloping the mold 50 atthe time of freeze-drying. In this way, the device 10 maintains atraceable link back to the human donor source.

To assist in the reconstitution of the freeze dried plasma material 16,an aseptic dense sphere of an inert material such as, but not limitedto, glass, polyvinyl chloride or high density polyethylene may be addedto the inside of the chamber 12 prior to its closure.

The reconstituting liquid 18 (in the representative embodiment, gas-freewater) is introduced into the second chamber 14. The vacuum port 66 andadministration port 68 are connected to feed lines 80 and 82,respectively, as FIG. 20 shows. Gas in the chamber 14 is removed byapplication of aseptic vacuum.

The vacuum port 66 is sealed and the tubing 80 is removed. The requiredaliquot (e.g., approximately 250 ml) of degassed water for injection isadded to the chamber 14 through the administration port 68. The tubing82 is removed and the administration port 68 is then sealed with theconventional septum or frangible membrane assembly or a conventionscrew-lock luer fitting 70, which accommodate coupling of theadministration set 68 to the port 68 at time of transfusion.

To assist in the reconstitution of the freeze dried plasma, an asepticdense sphere of an inert material such as, but not limited to, glass,polyvinyl chloride or high density polyethylene may be present insidethe second chamber 14.

As FIG. 21 shows, after packaging the freeze-dried material 16 and thereconstituting liquid 18 in the manner just described, the wall of thedevice 10 is plicated in the region of the sealing wall 22, aspreviously described, and the outer skirt 40 attached. The overwrap 20can be applied, as shown in FIG. 1, if desired.

The device 10 is ready for storage, transport, and use

III. Reconstitution and Administration of the Freeze-Dried Material

The device 10 makes possible a purposeful two step manipulation inanticipation of reconstituting the freeze-dried material 16.

In the first step (shown in FIG. 8), the tear member 42 is pulled toopen and remove the skirt 40, which places the sealing wall 22 of thedevice 10 in the ready for use configuration shown in FIG. 6. In thesecond step (shown in FIG. 9), the tear member 32 is pulled to open theseptum 20 (which FIG. 7 shows in greater detail). The region 24 of thesealing wall 22 is thereby opened.

When the region 24 is opened, the caregiver can apply pressure to thesecond chamber 14 to express the reconstituting liquid 18 from thesecond-chamber 14 into the first chamber 12 (see FIGS. 10 and 11),thereby beginning the reconstitution of the freeze-dried material 16.More particularly, with the region 24 opened, the caregiver can applypressure to the second chamber 14 (as FIG. 10 shows) and not the firstchamber 12. As FIGS. 10 and 11 show, the pressure differential betweenthe second chamber 14 and the first chamber 12 expels the liquid 18 fromthe second chamber 14, through the valve 28 (which yields in response tothe pressure differential to open in the direction of the first chamber12, as FIG. 11 shows), and into the first chamber 12. The expelledliquid 18 mixes with the freeze-dried material 16 in the first chamber12, beginning the reconstitution.

As FIG. 12 show, shaking the device 10 accelerates the mixing of liquid18 and freeze-dried material 18 in the first chamber 12.

When the region 24 is opened, the caregiver can subsequently applypressure to the first chamber 12 to express the material 16, now atleast partially reconstituted in the liquid 18, from the first chamber12 into the second chamber 14 (see FIGS. 13 and 14). Reconstitution ofthe freeze-dried material 16 is advanced. More particularly, as FIG. 13shows, the caregiver can now apply pressure to the first chamber 12 (asFIG. 13 shows) and not the second chamber 14. As FIGS. 13 and 14 show,the pressure differential between the first chamber 12 and the secondchamber 14 expels the mixture of the liquid 18 and the freeze-driedmaterial 16 from the first chamber 12, through the valve 28 (whichyields in response to the pressure differential to open in the directionof the second chamber 14, as FIG. 14 shows), and back into the secondchamber 14. The expelled liquid 18 continues to mix with thefreeze-dried plasma material 18, furthering the reconstitution of thematerial 18.

As FIG. 15 shows, shaking the device 10 further accelerates the mixingof water and freeze-dried plasma in the second chamber 14.

The material 16 reconstituted in the liquid 18 can be passed back andforth between the two chambers 12 and 14 by alternating pressure on thechambers 12 and 14, with intermediate shaking, until the desired degreeof mixing occurs, at which time the mixture is ready for transfusion.More particularly, the caregiver can proceed to squeeze one chamber andnot the other, to expel the mixture of the liquid 18 and freeze-driedmaterial 18 back and forth between the chambers 12 and 14, with periodicshaking, until the desired degree of mixing and reconstitution of theplasma is accomplished.

At this point (as FIG. 16 shows), the caregiver can couple theadministration fitting 70 of the device 10 to the fluid administrationset 72. The reconstituted plasma is transfused by gravity flow through aphlebotomy needle 84 into the circulatory system of an individual.

The administration fitting 70 can further include a static mixing tube86 (as shown in FIG. 16), to assist in continued reconstitution ofplasma aliquot 5 with water 7 during transfusion.

The device 10 as described provides:

i) long term stable containment of a freeze-dried material such asfreeze-dried human plasma;

ii) eventual rapid reconstitution of the freeze-dried material with areconstituting liquid for injection; and

iii) eventual delivery of the reconstituted freeze dried material to atrauma victim in a safe, sterile manner.

IV. Other Representative Embodiments

A. Dual Containers With Intermediate Valve Passage

FIG. 22 shows another representative embodiment of a device 100 forstoring an administering a freeze-dried material. The device 100comprises a first collapsible container 102 and a second collapsiblecontainer 104, joined by an intermediate normally closed valve assembly106.

The device 100 shares many of the technical features of the device shownin FIG. 1, albeit the particular structure differs. The first container102 comprises the dry chamber 12 as previously described, and is sizedand configured to contains an aliquot of a freeze-dried material 16,such as a freeze-dried single donor unit of human plasma.

The second container 104 comprises the wet chamber 14, as previouslydescribed, and is sized and configured to contain a reconstitutingliquid 18 for the freeze-dried material 16. As before described, thereconstituting material 18 can comprise, e.g., degassed, sterile water.

In use, the sterile water in the wet chamber 14 is mixed with thefreeze-dried plasma in the dry chamber 12 to provide plasma fortransfusion. The plasma is reconstituted and administered on site usingthe device 10.

As before described, the first container 102 is sized and configured tomaintain the freeze-dried material 16, prior to its reconstitution, in avacuum packed, aseptic, moisture-free and low concentration oxygenenvironment, preferably accommodating long term storage, e.g., at least2 years at room temperature. Stored in this environment, thefreeze-dried material 16 retains its desired qualities for transfusion.

As also before described, the second container 104 is sized andconfigured to maintain the reconstituting liquid 18, prior to its mixingwith the freeze-dried material 16, in an aseptic environment and at alow gas concentration, preferably accommodating long term storage, e.g.,at least 2 years at room temperature.

The volume of each of the containers 102 and 104 is preferablyapproximately 50% larger than the volume of the freeze-dried material 16in the first chamber 12. This provides ample volume within the device 10for mixing the freeze-dried material 16 and reconstituting liquid 18,either in the first container 102, or the second container 104, as willbe described in greater detail later.

The containers 102 and 104 may be made, e.g., of an inert medical gradeplastic material, such as polyvinyl chloride, polyethylene,polypropylene, or high density polyethylene. One or both of thecontainer 102 and 104 can comprise a multi-laminate of polymer layersfor greater durability, e.g., to resist tearing and puncturing thatcould be encountered in normal handling.

The material of the containers 102 and 104 can be selected to betransparent, if desired, to allow visual inspection of the contents ofthe chamber 12 and 14. The material in the first container 102 can beselected to provide a gas-impermeable barrier, such as a metallized,reduced gas-permeability coating, or a metal laminate. In this case, thewall of the first chamber may be opaque.

As before described, the device 100 may be enveloped prior to use by avacuum sealed over-wrap 20 (shown in phantom lines in FIG. 22), made,e.g., a metallized, gas impermeable material. The over-wrap 20 enhancesshelf-stability.

In the alternative representative embodiment shown in FIG. 22, the valveassembly 106 includes a pressure sensitive valve 108 enclosed within aflexible tubular valve passage 110, which extends between the twocontainers 102 and 104. The valve 108 can take the form, e.g., of ashort duck bill or two way flap valve. The valve 108 is sized andconfigured to normally resist flow communication between the twocontainers 102 and 104. However, the valve 108 is sized and configuredto resiliently yield in response to a difference in fluid pressurebetween opposite sides of the valve 108 (in the same manner as the valve28 shown in FIGS. 11 and 14). In response to the pressure differential,the valve 108, like the valve 28, opens in the direction of the fluidpressure differential, from the region of higher pressure toward theregion of lower pressure.

The regions of the wall of the containers to which the valve passage 110is joined normally close communication between the containers 102 and104 through the valve passage 110.

An outer tear-away skirt 112 is wrapped around the mid-regions of thecontainers 102 and 104 and the intermediate valve passage 110. The skirt112 serves to overlay and protect the components of the valve assembly106 prior to use. At least one region of the skirt 112 iscircumferentially attached about an exterior wall of each container 102and 104, e.g., by adhesive, either in the region of the first chamber,the second chamber, or both.

As FIG. 23 shows, within the outer skirt 112, the mid-regions of thecontainers 102 and 104, and the valve passage 110 itself, are desirablyplicated or pleated or otherwise bunched together, shortening the lengthof each container 102 and 104 and the valve passage 110. Alternatively,the placations can be performed in the walls of the containers 102 and104 and/or valve passage 110. The presence of the overlaying skirt 112serves to isolate the valve passage 100 from unintended contact duringtransport and prior to use.

As FIG. 23 shows, the walls of each container 102 and 104 that overlayopposite ends of the valve passage 110 each includes an integrated tearmember 112. As FIG. 23 shows, each integrated tear member 112 is coupledby an internal pull string 114 to an adjacent side wall of therespective container 102 and 104. The internal pull string 114 isnormally held in slight tension when the device 100 is in the plicatedcondition shown in FIG. 22 (i.e., when the mid-regions of the containers102 and 104, and the valve passage 110 itself, are plicated and held inthis condition by the outer shirt 112). When the device 100 is in theplicated condition, the tension on the internal pull string 114 is notsufficient to affect the tear member 112. The walls of each container102 and 104 that overlay opposite ends of the valve passage 110 remainclosed. When the device 100 is in the plicated condition, the chambers12 and 14 and their contents remain isolated and separated prior to use.

As FIG. 24 shows, the skirt 112 can be torn and removed by operation ofan integrated tear member 116 (in the manner shown in FIG. 3), to placethe device 100 in the condition shown in FIG. 24. As FIG. 24 shows, uponremoval of the skirt 112, the placations of the walls of the containers102 and 104 and valve passage 110 are relieved, and the device 100lengthens.

As FIG. 25 shows, when the device 100 lengthens, tension on the internalpull string 114 is increased. The increased tension is sufficient toactivate the tear member 112, tearing open regions 116 of the walls onopposite ends of the valve passage 110 (as FIG. 25 shows). The openregions 116 place the first and second chambers 12 and 14 intocommunication through the valve passage 110.

With the regions 116 opened, the caregiver can proceed to manipulate thedevice 100 in the same manner previously described with respect todevice 10 (as shown in FIGS. 10 to 16). The caregiver creates the fluidpressure differential across the valve 108 by selectively squeezing onecontainer and not the other container. Fluid is expelled in response tothe fluid pressure differential through the valve 108 from the containerthat is squeezed into the container that is not squeezed to mix andreconstitute the freeze-drive material for administration. Transfer ofmaterials in opposite directions between the chambers 12 and 14 throughthe valve passage 110 as a result of the manipulation of the containers102 and 104 is shown in FIGS. 26 and 27.

B. Dual Containers With Transfer Set

FIG. 30 shows a representative embodiment of a system 200 for storing anadministering a freeze-dried material. The system 200 comprises a firstcollapsible container 202 and a second, separate collapsible container204. The system 200 further comprises a transfer set 206 forestablishing fluid communication between the first and second containers202 and 204.

The system 200 shares many of the technical features of the devicesshown in FIGS. 1 and 22, albeit the particular structure differs.

The first container 202 comprises the dry chamber 12 as previouslydescribed, and is sized and configured to contains an aliquot of afreeze-dried material 16, such as a freeze-dried single donor unit ofhuman plasma. To maintain a direct traceable link between the sourceplasma and the material 16 in the chamber 12, the container 202preferably includes a bar coding and tagging 54 (see FIG. 30), which isindicative of the human plasma identification (source, blood type, dateof collection, etc.). In this way, the container 202 maintains atraceable link back to the human donor source.

The second container 204 comprises the wet chamber 14, as previouslydescribed, and is sized and configured to contain a reconstitutingliquid 18 for the freeze-dried material 16. As before described, thereconstituting material 18 can comprise, e.g., degassed, sterile water.

In use (see FIG. 31), using the transfer set 206, the sterile water inthe wet chamber 14 is mixed with the freeze-dried plasma in the drychamber 12 to provide plasma for transfusion. The plasma isreconstituted and administered on site using the system 200.

As before described, the first container 202 is sized and configured tomaintain the freeze-dried material 16, prior to its reconstitution, in avacuum packed, aseptic, moisture-free and low concentration oxygenenvironment, preferably accommodating long term storage, e.g., at least2 years at room temperature. Stored in this environment, thefreeze-dried material 16 retains its desired qualities for transfusion.

As also before described, the second container 204 is sized andconfigured to maintain the reconstituting liquid 18, prior to its mixingwith the freeze-dried material 16, in an aseptic environment and at alow gas concentration, preferably accommodating long term storage, e.g.,at least 2 years at room temperature.

The volume of each of the containers 202 and 204 is preferablyapproximately 50% larger than the volume of the freeze-dried material 16in the first chamber 12. This provides ample volume within thecontainers 202 and 204 for mixing the freeze-dried material 16 andreconstituting liquid 18, either in the first container 202, or thesecond container 204, or both, as will be described in greater detaillater.

The containers 202 and 204 may be made, e.g., of an inert medical gradeplastic material, such as polyvinyl chloride, polyethylene,polypropylene, or high density polyethylene. One or both of thecontainer 202 and 204 can comprise a multi-laminate of polymer layersfor greater durability, e.g., to resist tearing and puncturing thatcould be encountered in normal handling.

The material of the containers 202 and 204 can be selected to betransparent, if desired, to allow visual inspection of the contents ofthe chamber 12 and 14. The material in the first container 202 can beselected to provide a gas-impermeable barrier, such as a metallized,reduced gas-permeability coating, or a metal laminate. In this case, thewall of the first chamber 12 may be opaque.

Each container 202 and 204 may be enveloped prior to use by a vacuumsealed over-wrap 208 (shown in phantom lines in FIG. 30), made, e.g., ametallized, gas impermeable material. The over-wrap 208 enhancesshelf-stability. The transfer set 206 also is desirably packaged in asterile over-wrap 208 prior to use (as shown in phantom lines in FIG.31).

The transfer set 206 includes plastic needles or spikes 210 at each end.An outer tear-away skirt or cap 216 can placed or wrapped around eachneedle or spike 210 to preserve sterility until the instant of use.

In use, the needles or spikes 210 are sized and configure to punctureconventional pierceable membranes 212 located within port tubes 214coupled in fluid communication with each container 202 and 204. Eachmembrane 212 normally seals the respective container 202 and 204 untilpierced by the respective needle or spike 210 of the transfer set 206.Once pierced by the needle or spike 210, fluid communication is openedthrough the port tube 214.

With the port tubes opened 214 opened, the caregiver can proceed tomanipulate the system 200 to transfer the reconstituting liquid 18 fromthe second container 204 into contact with the freeze-dried material 16,as FIG. 31 shows, The caregiver can create a fluid pressure differentialacross the transfer set 206 by selectively squeezing one container andnot the other container. Fluid is expelled in response to the fluidpressure differential through the transfer set 206 from the containerthat is squeezed into the container that is not squeezed to mix andreconstitute the freeze-drive material for administration. Transfer ofmaterials in opposite directions back and forth between the chambers 12and 14 can proceed as necessary to reconstitute the freeze-driedmaterial, at which time administration can occur.

At this time, the caregiver can couple the administration fitting 70(shown coupled to the first container 202) to an appropriateadministration set, for transfer of the reconstituted material to thecirculatory system of an individual, as shown in FIG. 31, in the samemanner as before described with reference to FIG. 16. The administrationfitting 70 can also be coupled to the second container 204, or both thefirst and second containers 202 and 204.

C. Alternative Ways to Package the Reconstituting Liquid

FIGS. 28A/B and 29A/B shows alternative ways to package thereconstituting liquid 18 in a device 10 or device 100 as previouslydescribed. In these alternative ways, it is not necessary to use theadministration port 68 to convey the reconstituting liquid 18, but canbe closed and sealed in a pre-packaging operation.

In one alternative representative embodiment (see FIG. 28A/B), the wetchamber 14 includes two packaging ports 120 and 128. In use (see FIG.28A), the first port 120 is coupled to a source 124 of thereconstituting liquid 18 via a first inline valve 122. The second port128 is coupled to a vacuum source 125 via a second inline valve 126.

As shown FIG. 28A, the first valve 122 is closed and the second valve126 is opened. A vacuum is applied to the interior of the chamber 14. Asshown in FIG. 26B, the first valve 122 is opened and the second valve126 is closed. The reconstituting liquid 18 is conveyed by gravity flowinto the chamber 14. Both packaging ports 120 and 128 are sealed.

In another alternative representative embodiment (see FIGS. 29A/B), thewet chamber 14 includes a single packaging port 130. In use (see FIG.29A), the port 130 is coupled to a source 132 of the reconstitutingliquid 18 and a vacuum source 134 through a two way valve 136.

As shown FIG. 29A, the two way valve 136 is operated to closecommunication with the liquid source 132 and to open communication withthe vacuum source 134. A vacuum is applied to the interior of thechamber 14. As shown in FIG. 29B, the two way valve 136 is operated toopen communication with the liquid source 132 and to close communicationwith the vacuum source 134. The reconstituting liquid 18 is conveyed bygravity flow into the chamber 14. The packaging port 130 is sealed.

In both arrangements, the administration port 68 can be inserted andsealed close in a pre-packing operation. The administration port 68 isnot used until it is time to administer the reconstituted freeze-driedmaterial, as shown in FIG. 16.

D. Alternative Ways to Package the Freeze-Dried Material

In an alternative embodiment, the material 16 can be freeze-dried insitu within the chamber 12. In this arrangement, as FIG. 33 shows, adevice 300 is compartmentalized by a sealing wall 22 into a chamber 12and a chamber 14, in the manner previously described. The sealing wall22 includes a septum 26 with pull string 34 and tab 38, as previouslydescribed.

To accommodate freeze-drying of the plasma within the chamber 12, thedevice 300 is made of a material that resists cracking at the lowtemperatures (e.g., below −33° C.) encountered during freeze-drying.Candidate materials include polyolefin materials, polyurethanematerials, polyurethane, elastomer materials, and polysiliconematerials. Polyvinyl chloride materials treated to withstand lowtemperatures can also be used.

The device 300 also includes first and second aseptic ports 302 and 304,which communicate with the first chamber 12. The first aseptic port 302,in use, conveys liquid plasma into the chamber 12 for freeze-drying. Thefirst port 302 is desirably normally closed by a pierceable membrane orseptum 314. The second aseptic port 304 is normally closed by ahydrophobic membrane 316. In use, the hydrophobic membrane 316accommodates the transport of vapors and gases into and out of thechamber 12 during and after the freeze-drying process, but otherwiseprevents liquid from leaving the chamber 12. The hydrophobic membrane316 can comprise, e.g., a nylon material, a polytetrafluoroethylene(PTFE) material, or a polypropylene material.

The device 300 also includes an aseptic port 306, which communicateswith the second chamber 14. The port 306, in use, conveys areconstituting fluid into the second chamber 14, as previously described(e.g., see FIGS. 29A and 29B). The first port 302 can also be normallyclosed by a pierceable membrane or septum 314.

An administration port 310 is also heat sealed in communication with thesecond chamber 14. The administration port 310, in use, conveysreconstituted material from the second chamber 14 for administration toan individual, as previously described.

As FIG. 34 shows, the first port 302 is sized and configured to beattached to tubing T coupled to a source of liquid plasma 312. In theillustrated embodiment, the tubing T includes a spike or needle 318 thatpierces the membrane 314 in the port 302, to open fluid communicationthrough the port 302 into the chamber 12.

Through the tubing T, a desired volume of liquid plasma is conveyed fromthe source 312 into the first chamber 12. Following the conveyance ofliquid plasma into the first chamber 12, the tubing T is removed, andthe port 302 is sealed closed. At this stage of processing, the secondchamber 14 remains empty, as FIG. 34 shows.

To maintain a direct traceable link between the source plasma and thematerial 16 that will be freeze-dried in the chamber 12, the device 300preferably includes a bar coding and tagging 54′ (see FIG. 31), which isindicative of the human plasma identification (source, blood type, dateof collection, etc.), and which replicates or is otherwise linked to thebar coding and tagging 54 placed on the source plasma bag 312. In thisway, the device 300 maintains a traceable link back to the human donorsource.

As shown in FIG. 35, one or more devices 300, with each chamber 12filled with liquid plasma, is placed inside a freeze dryer 320 on anaseptic freeze dryer shelf surfaces 322. Once loaded, the freeze dryercycle is started. This cycle generally cools the human plasma to near−45° C. and freezing for 2 to 8 hours, followed by cooling of the freezedryer condenser and application of vacuum to start the freeze dryingcycle. As a result, a freeze-dried human plasma cake 324 is formed insitu within the chamber 12 of each device 300 (see FIG. 36).

The parameters for the freeze-drying process have been previouslydescribed and are incorporated herein by reference. Generally, in theprimary freeze drying cycle, the temperature of the human plasma cake340 needs to remain below −33° C. (the collapse temperature) to maintainits integrity. When the moisture content of the cake 340 is below 5%weight per weight (w/w), a secondary drying cycle (the elevatedtemperature) is used to further lower the moisture content bysublimation of water vapor from the plasma cake, which vents through thehydrophobic membrane 316. Generally the combined primary and secondaryfreeze drying cycles will take at least 72 hours. At the conclusion ofthe freeze drying cycle, the freeze dryer vacuum is opened to anatmosphere of an oxygen-free, high purity inert gas such as nitrogen orargon.

Throughout the freeze drying process, the hydrophobic membrane 316within the port 304 accommodates passage of gases, e.g., water vapor asit sublimates from the liquid plasma during freeze-drying, but otherwiseprevents passage of liquid plasma from the chamber 12.

As shown in FIG. 36, after freeze-drying, the devices 300 with thefreeze dried cakes 324 in their chambers 12 are removed from the freezedryer 320.

Preferably, an aseptic vacuum is applied through the port 304. Uponachieving near 100 mTorr of pressure, the port 304 is heat sealedclosed. This evacuation process provides for the eventual ability to mixand reconstitute the human freeze dried plasma without introduction ofbubbles and without foaming. The vacuum would also cause the plasma cake324 to be compacted to a fine powder, forming the freeze-dried material16 within the chamber 12. The devices 300 can be maintained under anitrogen or argon blanket to exclude moisture and oxygen untilsubsequent processing.

Next (see FIG. 37), the reconstituting liquid 18 is introduced into thesecond chamber 14 through the port 306, for example, in manner shown inFIGS. 29A and 29B. The port 306 is then sealed.

As FIG. 38 shows, after packaging the freeze-dried material 16 and thereconstituting liquid 18 in the manner just described, the wall of thedevice 300 is plicated in the region of the sealing wall 22, aspreviously described, and an outer skirt 40 (with pull string 44 and tab46) attached, as also previously described. An overwrap can be applied,as shown in FIG. 1, if desired.

The device 300 is ready for storage, transport, and use.

It should be appreciated that liquid plasma could be freeze-dried insitu within the container 202 shown in FIG. 30 in the same manner asjust described.

The foregoing is considered as illustrative only of the principles ofthe invention. Furthermore, since numerous modifications and changeswill readily occur to those skilled in the art, it is not desired tolimit the invention to the exact construction and operation shown anddescribed. While the preferred embodiment has been described, thedetails may be changed without departing from the invention, which isdefined by the claims.

1. Apparatus comprising: a dry freeze-dried material, a reconstitutingliquid for the freeze-dried material, and a flexible container includingfirst chamber sized and configured to hold the freeze-dried material ina dry state, a second chamber sized and configured to hold thereconstituting liquid in a wet state, a sealing wall within the flexiblecontainer sized and configured to form a barrier between the firstchamber and the second chamber preventing contact between thefreeze-dried material and the reconstituting liquid, and at least onevalve assembly in the sealing wall operative to open a region of thesealing wall to establish fluid flow communication between the first andsecond chambers.
 2. Apparatus according to claim 1 wherein the valveassembly includes a pressure sensitive valve operative between anormally closed condition normally resisting fluid flow communicationbetween the first and second chambers and an opened conditionestablishing fluid flow condition communication between the first andsecond chambers in response to a pressure differential applied acrossthe valve.
 3. Apparatus according to claim 2 wherein the pressuresensitive valve comprises a flap valve.
 4. Apparatus according to claim1 wherein the valve assembly includes a normally closed septum operativein a normally closed condition maintaining closure between the first andsecond chambers and an opened condition establishing fluid flowcommunication between the first and second chambers in response to atleast a partially tearing of the septum.
 5. Apparatus according to claim4 wherein the septum includes a tear member coupled to a pulling memberto at least partially tear the septum.
 6. Apparatus according to claim 1wherein the valve assembly includes a pressure sensitive valve operativebetween a normally closed condition normally resisting fluid flowcommunication between the first and second chambers and an openedcondition establishing fluid flow condition communication between thefirst and second chambers in response to a pressure differential appliedacross the valve, and a normally closed septum associated with the valveoperative in a normally closed condition maintaining closure between thefirst and second chambers independent of the valve and an openedcondition establishing fluid flow communication between the first andsecond chambers in response to at least a partially tearing of theseptum and a pressure differential applied across the valve. 7.Apparatus according to claim 6 wherein the pressure sensitive valvecomprises a flap valve.
 8. Apparatus according to claim 6 wherein theseptum includes a tear member coupled to a pulling member to at leastpartially tear the septum.
 9. Apparatus according to claim 1 furtherincluding an outer skirt overlaying an exterior wall of the container ina region of the sealing wall.
 10. Apparatus according to claim 9 whereinthe outer skirt includes a tear member coupled to a pulling member totear the outer skirt for removal.
 11. Apparatus according to claim 9wherein at least a portion of the exterior wall of the containeroverlaid by the outer skirt includes placations.
 12. Apparatus accordingto claim 9 wherein the flexible container includes an integraladministration port for administering material from the container. 13.Apparatus according to claim 1 wherein the freeze-dried materialincludes freeze-dried human plasma.
 14. A method comprising providing aflexible container including first chamber holding a freeze-driedmaterial in a dry state, a second chamber holds a reconstituting liquidfor the freeze-dried material, the flexible container including aninterior sealing wall sized and configured to form a barrier between thefirst chamber and the second chamber preventing contact between thefreeze-dried material and the reconstituting liquid, and at least onevalve assembly in the sealing wall operative by manipulation to open aregion of the sealing wall to establish fluid flow communication betweenthe first and second chambers, manipulating the valve assembly to openthe region, and expressing the reconstituting liquid from the secondchamber through the valve assembly into the first chamber into contactwith the freeze-dried material.
 15. A method according to claim 14further including reconstituting the freeze-dried material bysuccessively expressing a mixture of the reconstituting liquid andfreeze-drive material between the first and second chambers, therebypreparing a reconstituted product.
 16. A method according to claim 15further including administering the reconstituted product directly fromone of the chambers to a recipient.
 17. A method according to claim 14wherein the freeze-dried material includes freeze-dried human plasma.18. A method comprising providing a flexible container including firstchamber holding a freeze-dried material in a dry state, a second chamberholding a reconstituting liquid for the freeze-dried material, theflexible container including an interior sealing wall sized andconfigured to form a barrier between the first chamber and the secondchamber preventing contact between the freeze-dried material and thereconstituting liquid, at least one valve assembly in the sealing walloperative by manipulation to open a region of the sealing wall toestablish fluid flow communication between the first and secondchambers, and an outer skirt overlaying an exterior wall of thecontainer in a region of the sealing wall and blocking manipulation ofthe valve assembly, removing the outer skirt to expose the valveassembly to manipulation, manipulating the valve assembly to open theregion, and expressing the reconstituting liquid from the second chamberthrough the valve assembly into the first chamber into contact with thefreeze-dried material.
 19. A method according to claim 18 furtherincluding reconstituting the freeze-dried material by successivelyexpressing a mixture of the reconstituting liquid and freeze-drivematerial between the first and second chambers, thereby preparing areconstituted product.
 20. A method according to claim 19 furtherincluding administering the reconstituted product directly from one ofthe chambers to a recipient.
 21. A method according to claim 18 whereinthe freeze-dried material includes freeze-dried human plasma.
 22. Amethod comprising providing a flexible container including firstchamber, a second chamber, and an interior sealing wall sized andconfigured to form a barrier between the first chamber and the secondchamber, and at least one valve assembly in the sealing wall operativeby manipulation to open a region of the sealing wall to establish fluidflow communication between the first and second chambers, preparing afreeze-dried material comprising freeze-dried human plasma, placing thefreeze dried material in the first chamber of the container, and placinga reconstitution liquid for the freeze dried material in the secondchamber of the container.
 23. A method according to claim 22 furtherincluding manipulating the valve assembly to open the region, andexpressing the reconstituting liquid from the second chamber through thevalve assembly into the first chamber into contact with the freeze-driedmaterial.
 24. A method according to claim 23 further includingreconstituting the freeze-dried material by successively expressing amixture of the reconstituting liquid and freeze-drive material betweenthe first and second chambers, thereby preparing a reconstitutedproduct.
 25. A method according to claim 24 further includingadministering the reconstituted product directly from one of thechambers to a recipient.